Neuroendocrine Complications of Cancer Therapy

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Contents 5.3 Detection and Screening ...... 67 5.1 Pathophysiology ...... 52 5.3.1 Signs and Symptoms Prompting 5.1.1 Normal Hypothalamic–Pituitary Axis . . . . 52 Immediate Evaluation ...... 67 5.1.1.1 Growth Hormone ...... 53 5.3.2 Surveillance of Asymptomatic Patients . . . 67 5.1.1.2 Gonadotropins ...... 53 5.3.3 GH Deficiency ...... 67 5.1.1.3 Thyroid-Stimulating 5.3.4 LH or FSH Deficiency ...... 67 Hormone ...... 54 5.3.5 Precocious Puberty ...... 68 5.1.1.4 Adrenocorticotropin ...... 54 5.3.6 TSH Deficiency ...... 69 5.1.1.5 Prolactin ...... 54 5.3.7 ACTH Deficiency ...... 69 5.1.2 Injury of the Hypothalamic–Pituitary Axis 5.3.8 Hyperprolactinemia ...... 70 in Patients with Cancer ...... 56 5.3.9 Diabetes Insipidus ...... 70 5.1.3 Contribution of Radiation 5.3.10 Osteopenia ...... 70 to Hypothalamic–Pituitary Axis Injury . . . 56 5.3.11 Hypothalamic Obesity ...... 70 5.2 Clinical Manifestations ...... 60 5.4 Management of Established Problems ...... 71 5.2.1 GH Deficiency ...... 60 5.4.1 GH Deficiency ...... 71 5.2.2 LH or FSH Deficiency ...... 60 5.4.2 LH or FSH Deficiency ...... 73 5.2.3 Precocious 5.4.3 Precocious Puberty ...... 74 or Rapid Tempo Puberty ...... 63 5.4.4 Hypothyroidism ...... 74 5.2.4 TSH Deficiency ...... 64 5.4.5 ACTH Deficiency ...... 75 5.2.5 ACTH Deficiency ...... 66 5.4.6 Hyperprolactinemia ...... 76 5.2.6 Hyperprolactinemia ...... 66 5.4.7 Diabetes Insipidus ...... 76 5.2.7 Diabetes Insipidus ...... 66 5.4.8 Osteopenia ...... 76 5.2.8 Osteopenia ...... 66 5.4.9 Hypothalamic Obesity ...... 77 5.2.9 Hypothalamic Obesity ...... 66 References ...... 77 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 52

52 Chapter 5 W. Leung · S. R. Rose · T. E. Merchant

Table 5.1. Anterior pituitary hormones and major hypothalamic regulatory factors

Pituitary hormone Hypothalamic factor Effect

Growth hormone Growth hormone-releasing hormone + Somatostatin – Prolactin Dopamine – Luteinizing hormone Gonadotropin-releasing hormone + Follicle-stimulating hormone Gonadotropin-releasing hormone + Thyroid-stimulating hormone Thyrotropin-releasing hormone + Somatostatin – Adrenocorticotropin Corticotropin-releasing hormone + Vasopressin +

Effects on the hypothalamus are either stimulatory (+) or inhibitory (–)

5.1 Pathophysiology 5.1.1 Normal Hypothalamic–Pituitary Axis The hypothalamic–pituitary axis (HPA) is the primary interface between the nervous system and the endocrine system.The actions and interactions of the endocrine and nervous systems constitute the major regulatory mechanisms for virtually all physiologic functions. The hypothalamus has extensive neural communications with other brain regions and regu- lates brain functions, including temperature, appetite, thirst, sexual behavior, and fear. The hypothalamus also contains two types of neurosecretory cells (Fig. 5.1): (1) neurohypophysial neurons, which transverse the hypothalamic–pituitary stalk and release vasopressin and oxytocin from their nerve end- ings in the posterior pituitary, and (2) hypophys- iotropic neurons, which release hormones into the portal hypophysial vessels to regulate the secretion of tropic hormones from the anterior pituitary. The six anterior pituitary hormones and their major hypo- Figure 5.1 thalamic regulatory factors are listed in Table 5.1. Diagrammatic representation of the hypothalamic– pituitary axis 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 53

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5.1.1.1 Growth Hormone

Growth hormone (GH) is a 191-amino acid polypeptide synthesized and secreted by the somatotrophs in the anterior pituitary gland in response to the hypothalamus releasing hormones, primarily GH-releasing hormone (GHRH) and somatostatin. GHRH secretion is usually steady, whereas somatostatin secretion is interrupted intermittently. Somatostatin con- tributes to the synthesis of GH in the pituitary but, paradoxically, inhibits GH release [45]. When somatostatin concentrations decrease, the tonic concentration of GHRH causes the release of GH into the systemic circulation. Factors such as neuropeptide Y, leptin, galanin, and ghrelin may also regulate GH secretion. In healthy children and adults, GH secretion is pulsatile,particularly during sleep,with two to a six pulses per night [50]. In adolescents, additional pulses occur during the day, and the pulses have higher peaks than those seen in children and adults (Fig. 5.2a). Circulating serum GH stimulates the production of insulin-like growth factor I (IGF-I) in all tissues. IGF-I mediates GH effects on growth, bone mineralization, and body composition (decreased fat deposi- tion, increased muscle mass) [71]. IGF-I is bound to IGF-binding proteins such as IGFBP3 and is trans- ported in the blood. IGF-I and IGFBP3 concentra- b tions are stable during the day and each reﬂects the integrated concentration of secreted GH. Figure 5.2 a,b a Changes with pubertal status in the normal daily pattern of growth hormone (GH), luteinizing hormone 5.1.1.2 Gonadotropins (LH), thyroid stimulating hormone (TSH), and adrenocorticotropin (ACTH) and cortisol secretion. b Normal Luteinizing hormone (LH) and follicle stimulating changes in LH and FSH levels from infancy to adoles- hormone (FSH) are glycoproteins both stored in the cence same cells in the anterior pituitary. Their overall pat- terns of secretion vary according to the age and gender of the person. The pituitary gland produces and secretes LH and FSH in a pulsatile manner in re- dren. In men, LH stimulates testosterone production sponse to a concordant episodic release of gonado- in the Leydig cells of the testes; normal spermatogen- tropin-releasing hormone (GnRH) from the hypo- esis requires both LH and FSH. In women, FSH stim- thalamus (Fig. 5.2a). The hypothalamic stimulus is ulates the production of estrogen and LH stimulates actively inhibited between 6 months of age and the the production of progesterone in the ovary. The LH onset of puberty (Fig. 5.2b). This inhibition can be surge near the end of the follicular phase of the men- disturbed by tumor mass, cranial surgery, or irradia- strual cycle is necessary to stimulate ovulation. De- tion, thereby resulting in precocious puberty in chil- velopment of the ovarian follicles is largely under 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 54

54 Chapter 5 W. Leung · S. R. Rose · T. E. Merchant

FSH control, and the secretion of estrogen from the throughout the day; it peaks before the person awak- follicle is dependent on both FSH and LH (see section ens in the morning (Fig. 5.2a), increases with stress, 5.2.2 for information on the normal development of and is inhibited by glucocorticoids. Because cortisol the gonads). secretion is regulated by ACTH,cortisol secretion has characteristics similar to the secretion of ACTH. In 5.1.1.3 Thyroid-Stimulating Hormone addition to the negative feedback of glucocorticoids, ACTH inhibits its own secretion (short loop feed- Thyrotropin, also known as thyroid-stimulating hor- back). mone (TSH), is a glycoprotein synthesized in the anterior pituitary.The secretion of TSH is stimulated by 5.1.1.5 Prolactin thyrotropin (or TSH)-releasing hormone (TRH) and inhibited by somatostatin and dopamine, secreted Prolactin (PRL) is a 198-amino acid polypeptide hor- from the hypothalamus. In persons older than 12 mone synthesized and secreted from the lactotrophs months of age,the TSH concentration is low in the af- of the anterior pituitary.A precursor molecule is also ternoon, rises dramatically (surges) after 1900 hours, secreted and can constitute as much as 10 %–20% of and reaches its highest concentrations between 2200 the PRL immunoreactivity in the plasma of healthy and 0400 hours (Fig. 5.2a) [51]. Thus, at least one persons.Hypothalamic control of PRL secretion (pri- third of the trophic inﬂuence of TSH on the thyroid marily through dopamine release) is different from gland occurs at night. TRH is necessary for TSH that of the other pituitary hormones in that the synthesis,post-translational glycosylation,and secre- hypothalamus inhibits, rather than stimulates, secretion of a fully bioactive TSH molecule from the pitu- tion of PRL. Thus, elevated PRL levels can be a use- itary [48]. Altered TSH glycosylation, resulting in ful marker of hypothalamic disorders that leave the altered bioactivity, is seen in mixed hypothyroidism pituitary intact. (central hypothyroidism with mild TSH elevation [5–15 mU/l]) [23, 49]. 5.1.2 Injury of the Hypothalamic–Pituitary Axis TSH stimulates the thyroid gland to produce in Patients with Cancer thyroxine (T4) and triiodothyronine (T3). T4 and T3 circulate in the blood stream bound to thyroxine- The hypothalamic–pituitary axis (HPA) is vulnerable binding globulin and albumin; only small amounts to damage by certain tumors, surgical trauma, irradi- are free or unbound. Free T4 undergoes intracellular ation, and chemotherapy [11, 60]. A summary of deiodination to form free T3,which interacts with the common risk factors for HPA disorders that develop DNA in a cell’s nucleus to inﬂuence cellular mRNA after cancer treatment is presented in Table 5.2. Pa- and protein synthesis. Free T4 also provides negative tients with tumors in the area of the HPA (e.g. cran- feedback to the hypothalamus and pituitary to mod- iopharyngioma or hypothalamic/chiasmatic tumor) ulate the secretion of TRH and TSH. are at particular risk for neuroendocrinopathy [15, 33]. Many HPA injuries are attributable to damage 5.1.1.4 Adrenocorticotropin caused by radiation therapy (see section 5.1.1.3). However, the incidence of pre-RT neuroendocrino- Adrenocorticotropin (ACTH) is a 39-amino acid pep- pathies in pediatric patients with brain tumors is tide hormone processed in the corticotrophs from a high. For example, out of 68 pediatric patients in one large precursor molecule, pro-opiomelanocortin. In study [32], 45 (66%) showed evidence of neuro- healthy individuals, hypothalamic corticotrophin-re- endocrinopathy before RT,including 15 of 32 patients leasing hormone and vasopressin are released in with tumors in the posterior fossa not adjacent to the two or three synchronous pulses per hour synergisti- HPA. Seventeen of the 45 patients (38%) revealed cally and stimulate the secretion of ACTH from the abnormalities in GH, 19 (43%) in TSH and 10 (22%) pituitary [9]. ACTH secretion is pulsatile and varies in ACTH. Six patients (13%) had aberrations in 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 55

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Table 5.2. Risk factors, diagnostic studies, and treatment options

Disorder Highest risk Diagnostic studies Treatment options

GH deficiency ≥ 18 Gy CRT IGF-1, IGFBP-3 Recombinant GH Pre-transplant CRT GH stimulation tests GHRH TBI GnRH agonist (if pubertal Young age maturity too advanced Tumor near HPA for height) Hydrocephalus Gonadotropin deficiency ≥ 30 Gy CRT LH, FSH, estradiol, or testosterone Estrogen / progestin (women) Tumor near HPA (4 to 8 AM) Testosterone (men) Bone age GnRH stimulation test Precocious puberty 18–24 Gy CRT LH, FSH, estradiol or testosterone GnRH agonist Female (4 to 8 AM) Young age Bone age radiograph Tumor near HPA Pelvic ultrasound (female) +/– GnRH stimulation test +/– GH stimulation test TSH deficiency ≥ 30 Gy CRT Free T4,TSH (8 AM) L-thyroxine TBI Nocturnal TSH surge Tumor near HPA TRH stimulation test Hydrocephalus ACTH deficiency ≥ 30 Gy CRT Cortisol (8 AM) Hydrocortisone Tumor near HPA Adrenal stimulation test Hydrocephalus Hyper-prolactinemia ≥ 50 Gy CRT Prolactin Dopamine agonists Tumor near HPA Diabetes insipidus Histiocytosis Simultaneous serum and urine Desmopressin Germinomas osmolarity after 8–12 hours Tumor or tumor- without fluid intake related cysts near HPA Osteopenia Low GH,TSH, DEXA or quantitative CT Calcium + vitamin D +/– or LH/FSH bisphosphonates High prolactin Hypothalamic obesity Young age (<6 years) Fasting insulin and glucose Diet and exercise ≥ 50 Gy (hypothalamus) Oral glucose tolerance test Ritalin or Dexedrine Tumor near HPA with insulin levels Metformin (monitor for hypoglycemia) Octreotide

GH, growth hormone; CRT, cranial radiation therapy;TBI, total body irradiation; HPA,hypothalamic–pituitary axis; IGF-1, insulin- like growth factor 1; IGFBP3, IGF binding protein 3; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; T4, thyroxine; TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone; ACTH, adrenocorticotrophin 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 56

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gonadotropin. In addition to these dysfunctions, ventricle and generalized diminished blood flow to patients who receive chemotherapy alone (with no sensitive regions of the brain. In one study, 59 chil- history of RT or CNS tumor) may be at risk for neu- dren with infratentorial ependymoma underwent roendocrinopathy.Of the 31 patients evaluated in one provocative testing for GH, thyroid hormone and study for altered growth and development, 48% had ACTH secretion abnormality prior to RT [22]. Ab- GH deficiency, 52% had central hypothyroidism, and normal testing was observed in 27 patients (46%), 32% had pubertal abnormalities [57]. with 30% of the 59 manifesting an abnormality in GH deficiency is commonly believed to be the first GH secretion. Serial measurements of ventricular hypothalamic–pituitary deficiency to emerge after size from the time of tumor diagnosis to one year af- injury to the HPA, followed by deficiencies of go- ter RT were recorded and modeled to show that ven- nadotropin, ACTH and TSH [60, 65]; however, these tricular size at the time of diagnosis could be used to deficiencies can occur in any order [11, 21, 35, 54, 67]. predict pre-irradiation endocrinopathy. In addition, Although the most common neuroendocrinologic change in ventricular size over time could predict GH abnormality in survivors of childhood cancer is GH deficiency prior to irradiation (Fig. 5.4). This study deficiency, hypothyroidism is at least as prevalent was remarkable because it demonstrated a relatively when sensitive testing methods are used [54]. The high rate of pre-irradiation endocrinopathy in a well- next most common alteration is in pubertal timing defined group and confirmed another important (precocious, rapid, delayed, or absent). ACTH defi- tumor-related cause of endocrinopathy. Moreover, it ciency, although less common than the other demonstrated the importance of managing hydro- disorders, has more serious consequences if it is not cephalus, which commonly occurs in children with detected. Osteopenia may result from hypothalamic– posterior fossa tumors. pituitary deficiency, particularly GH deficiency, Clinical data describing the neuroendocrine ef- hypothyroidism and hypogonadism. Hypothalamic fects of RT have been derived using generalized esti- injury resulting from tumor, surgery, or irradiation mates of radiation dose under conditions where the can result in unrelenting weight gain, termed “hypo- dose to the HPA was relatively homogeneous and dis- thalamic obesity.” crete. Examples include patients treated using single- dose or fractionated TBI (8–14 Gy), cranial irradia- 5.1.3 Contribution of Radiation tion for ALL (18 Gy and 24 Gy) and tumors of the to Hypothalamic–Pituitary Axis Injury sellar or parasellar region, in which the HPA was uni- formly included in the volume of the prescribed dose Radiation therapy (RT) is a significant contributor to (>50 Gy) (Fig. 5.5). For other diseases, the HPA may neuroendocrine complications commonly observed have been located within the irradiated volume for after treatment for CNS tumors, CNS preventative part or all of the treatment, or it may have been therapy for ALL and following total body irradiation. located in the gradient of dose (dose fall off),with the Similar complications are observed when the HPA is result that the HPA experienced only a fraction of the incidentally irradiated in the treatment of nasopha- daily dose administered (Fig. 5.6). These circum- ryngeal cancer, retinoblastoma, Hodgkin’s disease stances make it difficult to assign a dose to the HPA with involvement of Waldeyer’s ring or pediatric sar- or to determine the risk for late effects. The difficul- comas of the head and neck (e.g. parameningeal and ties become apparent when the patient is seen by the orbital rhabdomyosarcoma) (Fig. 5.3). The incidence endocrinologist years after treatment, when retro- of neuroendocrine sequelae after RT and also the spective dose calculations may be difficult to per- time to onset are difficult to predict. This is largely form. Newer radiation techniques employ 3-dimen- due to other contributors to HPA dysfunction, which sional imaging (CT and MR) in the planning process. may coincide temporally with the administration of The HPA and other normal tissues can be contoured RT. A notable example is hydrocephalus, which can on CT or MR data,and the dose can be calculated and cause a mass effect in the region of the anterior third reported more accurately. When correlated with ob- 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 57

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b d

Figure 5.3 a–d Radiation dosimetry taken from the treatment of children with orbital (a, b) and infratemporal fossa (c, d) rhabdomyosarcoma. The images illustrate cases in which the HPA is incidentally irradiated and may receive all or a portion of the prescription dose (arrow indicates location of hypothalamus) 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 58

58 Chapter 5 W. Leung · S. R. Rose · T. E. Merchant

a b

Figure 5.4 a,b The effect of hydrocephalus on pre-irradiation endocrinopathy in children with infratentorial ependymoma. a Probabili- ty of pre-irradiation endocrine deﬁciency based on frontal horn diameter measured at diagnosis. b Probability of pre- irradiation growth hormone (GH) deﬁciency based on change (slope) in the Evan’s index after diagnosis.The Evan’s index is the ratio of the distance between the most lateral extent of the frontal horns of the lateral ventricles and the width of the parietal brain at the same level

a b

Figure 5.5 a,b Homogeneous irradiation of the HPA, including: a a traditional treatment portal used for cranial irradiation in ALL, and b dosimetry from focal treatment of craniopharyngioma (arrow indicates location of hypothalamus) 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 59

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Figure 5.6 Dosimetry for a typical patient treated with conven- tional radiation therapy (40 Gy).This example illustrates b that the HPA receives only a portion of the total dose given to the primary tumor (arrow indicates location of Figure 5.7 a,b pituitary) HPA dose–volume data from patients treated with conformal radiation therapy. a Dose–volume curves repre- sent the percent–volume of the hypothalamus receiving a specific dose. b Correlation with change in peak jective measures of endocrine effects, this informa- GH (ATT/L-dopa) measured before, 6 and 12 months after radiation therapy results in an estimating equa- tion is becoming increasing valuable in predicting tion that can be used to predict GH deficiency up to the incidence of specific endocrine effects. Already 12 months after irradiation, based on the volume (V) this type of data has been modeled to predict peak received dose over specified intervals. ln [peak GH] × × GH secretion after radiation therapy [34]. In the = 3.072 – (0.00058 V0–2,000 cGy + 0.00106 V2,000–4,000 cGy + 0.00156 × V ) × time future,it may also be used to optimize RT for children 4,000–6,000 cGy (Fig. 5.7). In pediatric radiation oncology, reducing the side effects of treatment is an important goal. This can be For the remainder of children with brain tumors (this achieved primarily by limiting CNS irradiation to constitutes most children), CNS irradiation will re- those patients for whom the indications are clear and main a mainstay of the treatment. Incidental irradia- the benefits outweigh the risks. CNS irradiation has tion of the CNS will continue to be observed in chil- been effectively eliminated from the treatment of the dren with ocular tumors or tumors of the head and majority of children with ALL, and it has been elimi- neck destined to receive radiation therapy. Increased nated from a significant proportion of children with awareness of the importance of the hypothalamus low-grade glioma, who may be cured with surgery. as the effector organ in radiation-related neuro- 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 60

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endocrine sequelae and the use of 3-dimensional prospective study, all of the 21 children treated with a imaging in planning the treatment of tumors may total dose of more than 45 Gy for optic pathway tu- lead to a reduction in late effects.Reducing the risk of mor experienced GH deficiency and a significant complications can also be achieved by delaying the slowing of growth within 2 years after irradiation [6]. administration of radiation therapy [29, 60, 66], by At doses of cranial irradiation higher than 30 Gy (e.g. reducing the total dose, and by reducing the volume for suprasellar or posterior fossa tumor), the risk for irradiated. Dose reductions have been achieved for GH deficiency may be more than 80% by 10 years many tumors including retinoblastoma, pediatric after RT [59]. Cranial irradiation doses greater than soft-tissue sarcomas of the head and neck, and cer- 24 Gy result in GH deficiency in as many as two thirds tain CNS tumors including CNS germinoma.Volume of patients who receive this treatment [60, 62]. In reduction has been an important area of research in many younger children, GH deficiency results from the treatment of medulloblastoma, ependymoma, lower doses (>18 Gy). Doses of only 12–14 Gy, when low-grade astrocytoma, craniopharyngioma, and used for total body irradiation, combined with CNS germinoma [31, 36]. The risk of treating smaller chemotherapy and bone marrow transplantation, volumes must be carefully balanced with objective also pose a significant risk for GH deficiency [24, gains, documenting reductions in side effects in 26, 62]. prospective clinical trials.To this end,the inclusion of The growth rate is typically slow in children who endocrinology and its quantitative and relatively ob- are undergoing treatment for cancer and usually jective measures is essential. The risk of endocrine- improves (or catches up) after completion of cancer related complications should be carefully considered therapy (Fig. 5.8). Children whose growth rate does in planning radiation therapy, but it should not be not improve or whose growth rate is less than the used as a reason to avoid curative therapy. Careful mean for age and sex should be evaluated for growth follow-up and evaluation will lead to early interven- failure (Fig. 5.9). Causes of slow growth other than tion and provide the means to mitigate the conse- GH deficiency include hypothyroidism, radiation quences of irradiation. damage in growth centers of the long bones or the spine, chronic unresolved illness, poor nutrition, and depression. In individuals who have attained adult 5.2 Clinical Manifestations height, GH deficiency is usually asymptomatic [71], but may be associated with easy fatigability, de- 5.2.1 GH Deficiency creased muscle with increased fat mass, and in- Altered GH secretion is an important and well-docu- creased risk for cardiovascular disease [12, 16]. mented cause of poor growth in childhood cancer survivors, particularly in young children after sur- 5.2.2 LH or FSH Deficiency gery in the suprasellar region, cranial irradiation (≥18 Gy),or after total body irradiation (≥12 Gy).Hy- High doses of cranial radiation (≥30 Gy) are more pothalamic function is affected more than pituitary likely to cause hypothalamic GnRH deficiency and,as function [60]. In most patients with GH deficiency, a result, gonadotropin deficiency. In some patients, the deficiency occurs in the levels of hypothalamic high doses of cranial radiation leads to the preco- GHRH and somatostatin, with a resulting loss of the cious onset of puberty, due to the damage of GABA circadian pulsatile pattern of GH secretion. The radi- secretory neurons, andlater progresses to gonado- ation effect on GH secretion is dependent on fraction tropin deficiency due to the loss of GnRH secretory size and total hypothalamic dose–volume [34]. A cells. Lower doses of cranial radiation (18–24 Gy) are large fraction size of radiation administered over a more likely to cause damage only to the neurons short period of time is more likely to cause GH defi- secreting gamma-aminobutyric-acid (leading to dis- ciency than is the same total dose administered in inhibition and premature activation of GnRH neu- smaller fractions over a longer period of time. In one rons) and, therefore, to a rapid tempo in puberty or 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 61

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Figure 5.8 a,b a Complete catch-up growth in a boy after cancer therapy. b Growth in a girl after cancer therapy, without catch-up growth. Normal percentiles (5th, 50th, and 95th, as shown) are obtained from the National Center for Chronic Disease Prevention and Health Promotion [38]

precocious puberty [39, 40, 58]. In girls, the first signs Patients with gonadotropin deficiency may have a of puberty are a growth spurt and breast develop- delayed, interrupted, or absent puberty. The staging ment (palpable breast buds or thelarche), followed by of puberty is usually performed using the criteria of pubic hair growth and, after about 2 years, by menar- Tanner [69].In survivors of childhood cancer, we ini- che. In boys, the first sign of puberty is testicular en- tiate evaluation for delayed puberty in girls who show largement (testes length >2.5 cm), followed by penile no onset of breast development by 12 years of age or and pubic hair growth, followed by a growth spurt. In no menarche by 14 years of age; we initiate evaluation most studies of normal children, pubertal milestones for delayed puberty in boys who show no sign of are attained at ages that are normally distributed, testicular growth by 13 years of age.Boys treated with with a standard deviation (SD) of approximately agents that can cause infertility may have in normal 1 year [69]. Children entering puberty more than 2 pubertal hormones but reduced testicular volume, SDs earlier or later than average should be consid- due to damage to the seminiferous tubules and ered for endocrine evaluation. The average age that reduced sperm production. girls experience thelarche is 10 years, and the average age they experience menarche is 12.8 years; the average age when boys experience testicular growth is 11 years. 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 62

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᭣ Figure 5.9 a–f a Persistent growth failure in a boy after cancer therapy. b Later growth failure in a girl after recovery of normal growth. c Subtle persistent growth failure in a boy. d Growth in a girl with missed GH deﬁciency. e Growth in a boy with missed late onset GH deﬁciency. f Growth in a girl with central hypothyroidism

5.2.3 Precocious or Rapid Tempo Puberty 40]. Female sex and younger age at the time of cancer treatment are risk factors. In some children who have Precocious puberty is deﬁned as the onset of second- received cranial irradiation, puberty may start at a ary sexual development characteristics before age normal age but advance rapidly. Thus, tempo of pro- 8 years in girls and before age 9 years in boys [4]. De- gression as well as timing of onset must be moni- spite controversy that puberty prior to these ages tored. Rapid puberty is also caused by a loss of inhi- may occur in normal children [18], younger occur- bition of hypothalamic GnRH secretion. The out- rence than age 8 or 9 may be the only clue to the pres- come of early onset and/or rapid tempo of puberty is ence of pathology and should not be ignored [37]. short adult height. This is due to early bony matura- Pubic hair, acne, and body odor are not usually part tion, which causes children to lose 1 to 3 years of of the presentation of precocious puberty in children height growth (Fig. 5.10). younger than 4 years. Precocious puberty occurs in childhood cancer survivors who have lost inhibition of hypothalamic GnRH release as a result of tumor presence, elevated intracranial pressure, cranial surgery, or low dose cranial irradiation (18–24 Gy) [7, 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 64

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5.2.4 TSH Deficiency doses of 12–14.4 Gy) or craniospinal irradiation (fractionated total cranial doses higher than 30 Gy), Central hypothyroidism refers to thyroid hormone 15% had mixed hypothyroidism. deficiency caused by a disorder of the pituitary, hy- Secretory dysregulation of TSH after irradiation pothalamus, or hypothalamic–pituitary portal circu- may precede other endocrine disorders.For example, lation. In contrast, primary hypothyroidism refers to one year after receiving cranial irradiation for na- an under functioning of the thyroid gland itself. Pri- sopharyngeal carcinoma, 90% of the patients in one mary hypothyroidism is the most common form of study had a delayed TSH peak response to TRH, hypothyroidism in the general population. It may which is suggestive of central hypothyroidism [21]. occur in cancer survivors due to a family history Five years later, 64% of this cohort had GH deficien- of hypothyroidism as well as to cancer therapy. The cy, 31% had gonadotropin deficiency, and 27% had thyroid gland can be injured through irradiation or ACTH deficiency. In another investigation, seven autoimmune activity, leaving the central axis intact. children with brain tumors who were studied Central hypothyroidism in many survivors of child- prospectively after cranial irradiation (>30 Gy) had a hood cancer is characterized by blunted or absent blunted TSH surge before the onset of reduced GH nocturnal TSH surge, suggesting the loss of normal concentrations [65]. In another cohort of patients circadian variation in TRH release [44]. Using sensi- with central hypothyroidism, 34% had dysregulation tive testing of TRH and nocturnal TSH surge, Rose et of TSH secretion before the development of GH defi- al. [54] showed that central hypothyroidism, defined ciency [54]. by a blunted TSH surge, low or delayed TSH peak, Central hypothyroidism is difficult to diagnose be- or delayed TSH decline after TRH administration, is cause of its subtle clinical and laboratory presenta- more common than previously suspected. Central tion.It is particularly difficult to recognize in patients hypothyroidism has been found in as many as 65% of whose growth is complete, because slowed growth the survivors of brain or nasopharyngeal tumors, rate can no longer be used as a sign. Symptoms 35% of bone marrow transplant recipients, and of central hypothyroidism (e.g. asthenia, edema, 10%–15% of leukemia survivors [48, 49]. drowsiness, adynamia, skin dryness) may have a In cancer survivors, mixed hypothyroidism re- gradual onset and go unrecognized until thyroid flects separate injuries to the thyroid gland and the replacement therapy is initiated and the patient feels hypothalamus (e.g. radiation injury to both struc- better [14]. In addition to causing delayed puberty tures). TSH values are elevated and, in addition, the and slow growth (Fig. 5.9 f), hypothyroidism may secretory dynamics of TSH are abnormal, with a cause fatigue, dry skin, constipation, increased sleep blunted or absent TSH surge or a delayed peak requirement, and cold intolerance. response (i.e.>45 minutes) to TRH [53,54].This con- trasts with primary hypothyroidism in which the TSH surge and the timing of the response to TRH are normal. In a study of 208 childhood cancer survivors referred for evaluation for possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 (7%) [54].All of the patients with mixed hypothyroidism had free T4 concentrations in the low normal range four had no elevation of basal TSH but ᭤ elevated peak TSH and seven had basal elevated TSH Figure 5.10 a–d but peak response to TRH in the normal range. Both a Growth in a girl with precocious puberty. b Growth in the TRH test and the TSH surge test were required a girl with rapid/early puberty. c Growth in a boy with rapid/early puberty. d Growth in a girl with GH defi- to make the diagnosis [54]. Among patients who ciency hidden by precocious puberty (no growth spurt) received total body irradiation (fractionated total 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 65

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5.2.5 ACTH Deﬁciency 5.2.7 Diabetes Insipidus

ACTH deficiency is less common than other neu- Diabetes insipidus may be caused by histiocytosis, roendocrine deficits but should be suspected in pa- germinomas, surgical trauma or CNS-involved tients who have a history of brain tumor (regardless leukemia. Patients with diabetes insipidus usually of therapy modality), cranial irradiation, GH defi- present with obvious symptoms of excessive thirst ciency, or central hypothyroidism [11, 56]. Although and urination with nocturia or enuresis. However, uncommon, ACTH deficiency can occur in patients diabetes insipidus may not be recognized until who have received intracranial radiation that did not affected patients have dehydration during an inter- exceed 24 Gy. It has been reported to occur in fewer current illness. The urine remains clear in color than 3% of patients after chemotherapy alone [56,57]. throughout the day. In patients with CNS-involved The symptoms of central adrenal insufficiency can leukemia, severe hypernatremic dehydration can be subtle. They include poor weight gain, anorexia, occur if the CNS lesion also affects the centers for easy fatigability, and poor stamina. In patients who thirst regulation. have ACTH deficiency,as opposed to primary adrenal insufficiency, symptoms of salt craving, electrolyte 5.2.8 Osteopenia imbalance, vitiligo, and hyperpigmentation usually are not observed. More overt manifestations of com- Osteopenia may result from HPA abnormality (GH plete ACTH deficiency include weight loss and shak- deficiency,hypothyroidism, hypogonadism or hyper- iness that is relieved by eating (hypoglycemia). Signs prolactinemia) in association with the direct effects of adrenal crisis at times of medical stress include of glucocorticoid therapy, methotrexate, inactivity weakness, abdominal pain, hypotension, and shock. and dietary changes. Osteopenia may present with Patients with partial ACTH deficiency may have fractures or may be asymptomatic. Among 141 sur- only subtle symptoms unless they become ill. Illness vivors of childhood leukemia in one study, 30 (21%) can disrupt these patients’ usual homeostasis and had abnormally low bone mineral density (BMD cause a more severe, prolonged or complicated >1.645 SD below the mean of normal population). course than expected.As in complete ACTH deficien- Risk factors for bone mineral decrements included cy, incomplete or unrecognized ACTH deficiency can male gender, Caucasian race and cranial irradiation. be life-threatening during concurrent illness. BMD was inversely correlated with the cumulative dose of cranial irradiation or antimetabolites [20]. 5.2.6 Hyperprolactinemia 5.2.9 Hypothalamic Obesity Hyperprolactinemia has been described in patients who have received doses of radiation to the hypothal- Hypothalamic damage from a tumor or cancer treat- amus greater than 50 Gy, as well as in patients who ment can also result in hypothalamic obesity – unre- have undergone surgery disrupting the integrity of lenting weight gain that does not respond to caloric the pituitary stalk. Hyperprolactinemia may result in restriction or exercise – attributable to ventromedial delayed puberty. In adult women, hyperprolactine- hypothalamus damage and abnormality in leptin, mia may cause galactorrhea, menstrual irregulari- ghrelin and insulin feedback [27]. In rodents, hypo- ties, loss of libido, hot flashes, infertility and osteope- thalamic obesity can be suppressed by pancreatic nia. In adult men, impotence and loss of libido can vagotomy to prevent insulin hypersecretion. Recent result. Primary hypothyroidism may lead to hyper- studies in patients with cranial insult confirmed in- prolactinemia as a result of hyperplasia of thy- sulin hypersecretion as one of the major mechanisms rotrophs and lactotrophs, probably due to TRH hy- for the development of hypothalamic obesity [28]. In persecretion. The PRL response to TRH is usually a study of 148 survivors of childhood brain tumors, exaggerated in these patients. the risk factors for hypothalamic obesity included 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 67

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age at diagnosis of cancer (<6 years), tumor location ▬ Assessment of nutritional status, adequacy of (hypothalamic or thalamic), tumor histology (cran- dietary calcium and vitamin D intake iopharyngioma, germinoma, optic glioma, prolactin- ▬ Ascertainment of Tanner stage, testicular volume oma or hypothalamic astrocytoma), hypothalamic (as measured by Prader orchidometry), and inter- irradiation (>51 Gy) and the presence of endo- pretation of whether the pubertal status and crinopathy (deficiency of GH, sex hormones, ACTH tempo of progression are appropriate for age and or vasopressin) [27, 29]. No effects were noted on height body mass index from V-P shunting, steroid use (<6 ▬ Review of organ systems (Table 5.3) months) or chemotherapy. Thus, any form of hypo- ▬ Measurement of the serum concentrations of free thalamic damage, whether due to tumor, surgery or T4 and TSH RT, is a regional-specific primary risk factor for the development of obesity. 5.3.3 GH Deficiency GH deficiency should be considered in children who 5.3 Detection and Screening have a slow growth rate and a medical history that indicates they are at risk for GH deficiency [17, 72]. 5.3.1 Signs and Symptoms Prompting Bone age, as determined by radiographic analysis of Immediate Evaluation the left hand and wrist, should be determined, and Survivors of childhood cancer with any of the follow- IGF-I and IGFBP3 should be measured in children ing 10 symptoms should be referred for a neuroen- who are growing too slowly. A combination of previ- docrinopathy evaluation: ous cranial or total body irradiation, slow growth (1) slow growth rate or failure to show catch up rate, abnormal weight gain, no intercurrent illness, growth; (2) failure to thrive; (3) obesity; (4) persistent delayed bone maturation, and low plasma levels of fatigue or anorexia; (5) polydipsia and polyuria; (6) IGF-I and IGFBP3 (i.e. concentrations lower than 1 severely dry skin or thin and brittle hair; (7) altered SD from the mean for the child’s age group) are high- timing of onset of puberty (e.g. signs of puberty be- ly suggestive of GH deficiency. The diagnosis should fore age 9 years or, in patients with short height, fail- be confirmed by GH stimulation testing [52]. Evalua- ure to enter puberty by age 12 years in girls and tion of the nocturnal profile of GH secretion is rarely 13 years in boys); (8) abnormal tempo of puberty necessary to make the diagnosis, but, after cranial (e.g. rapid or interrupted progression of puberty); irradiation, the study may be abnormal in sympto- (9) galactorrhea; and (10) abnormal menstruation or matic children who have normal stimulated GH sexual function. results [2]. Recognition of GH deficiency in adults is more dif- 5.3.2 Surveillance of Asymptomatic Patients ficult, because slow growth rate is not available as a marker. Recognition depends on clinical suspicion Asymptomatic patients who are at risk for neuroen- related to medical history. Diagnosis of GH deficien- docrinopathy (Table 5.2) should undergo the follow- cy in adults requires evidence of other hypothal- ing routine yearly surveillance: amic–pituitary hormone deficiencies and a low peak response to GH stimulation tests [1]. ▬ Accurate measurements of height,or arm span (an alternative estimate of height) if the patient received total body or spinal irradiation or has scol- 5.3.4 LH or FSH Deficiency iosis or kyphosis (factors that lead to reduced During the range of ages that puberty is normally ex- spinal bone growth or measurement) pected to occur, breast development, pubic hair ▬ Accurate measurement of weight and assessment growth and distribution, and and vaginal estroge- of body mass index nization should be monitored every 6 months in girls 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 68

68 Chapter 5 W. Leung · S. R. Rose · T. E. Merchant

Table 5.3. Review of systems

The child currently has these problems (circle each one that the child has): Activity: overactive, unable to exercise, poor stamina, frequently tired Sleep: daytime sleepiness, difficulty falling asleep, waking after falling asleep Appetite: loss of appetite, excessive appetite, weight gain, weight loss increased thirst, decreased thirst, difficulty swallowing Mood: rapid changes in mood, dizziness, depression, hard to get started doing task Neurology: headaches, vision change, seizures change in ability to smell, change in taste of foods balance difficulty, weakness, poor coordination, muscles too tight, spasticity disruptive behavior, unable to finish tasks poor attention, poor concentration, can’t remember things Skin/hair: hair loss, excess hair, dry skin, oily skin, cold intolerance, heat intolerance Heart: rapid heart beat, irregular heart beat, slow heart beat, edema in feet Abdomen: Nausea, vomiting, diarrhea, constipation, abdominal pain Urinary: frequent urination, bed wetting, night awaking to urinate Puberty/breast: breast growth, age of first breast buds ______soreness under nipples, fluid from nipples age of first pubic hair ______, age of first deodorant use ______age of first period ______, menses irregular interrupted puberty, rapid tempo of puberty Sexual function: loss of libido, impotence, decreased nocturnal emissions

at risk of having LH or FSH deficiencies. Similarly, ples should be drawn between 4 and 8 AM, shortly testes size, pubic hair growth and distribution, after nighttime pulses of LH have been occurring and phallus length should be monitored every 6 (Fig. 5.2a). months in boys. Testicular size in some boys may be small for their genital maturation because of RT- 5.3.5 Precocious Puberty or chemotherapy-induced damage to the seminiferous tubules. Precocious puberty is diagnosed if the onset of sec- Measurement of bone age, serum LH, FSH and sex ondary sexual development occurs before age eight steroid (testosterone or estradiol) should be per- in girls or nine in boys. A radiograph of the left hand formed in children with a delayed or interrupted pro- and wrist shows bone age that is advanced compared gression of puberty. Evaluation by an endocrinolo- with chronological age; however, bone age may be gist is warranted in the absence of the progression of consistent with chronological age, or even delayed, in puberty by 1 year after the completion of cancer ther- a child who has concurrent GH deficiency or hy- apy in girls >13 years of age, and in boys >14 years of pothyroidism and who has not undergone a growth age. Stimulation testing with synthetic GnRH pro- spurt. (Fig. 5.10 d). Because concurrent GH deficien- vides more information than does a single, random- cy may not be discovered until after successful treat- ly- drawn level of LH and FSH.As an alternative to the ment of precocious puberty (Fig. 5.10 d),we routine- GnRH stimulation test, a serum sample for LH, FSH ly perform provocative GH testing in patients with and testosterone or estradiol may be used. The sam- precocious puberty who have a history of cancer. 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 69

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5.3.6 TSH Deﬁciency 5.3.7 ACTH Deﬁciency

We suggest that routine annual measurements of For patients at risk for ACTH deficiency (e.g. those TSH and free T4 be taken in all patients who have who received ≥30 Gy irradiation to HPA), surveil- received cranial irradiation. This is because the lance should include an annual measurement of plas- symptoms of central hypothyroidism are often sub- ma cortisol concentration at 0800 hours. If the corti- tle, and TSH secretory dysregulation after irradiation sol level is below 18 µg/dl (497 nmol/l) at 0800 hours, may precede other endocrine disorders [21, 54]. The then further evaluation is needed and should be di- diagnosis of hypothyroidism may be delayed in as rected by an endocrinologist. The optimal evaluation many as one third of all childhood cancer patients for ACTH deficiency is controversial [55]. Measure- if TSH secretion is not tested until GH deficiency be- ment of the basal plasma ACTH concentration usual- comes apparent. Such a delay may be acceptable in a ly can distinguish primary adrenal disease from cen- minimally symptomatic adult. In children, however, tral adrenal insufficiency,provided the ACTH assay is the potential functional implications of hypothy- reliable and there is no urgency in establishing the roidism and lost growth opportunity are not accept- cause of adrenal insufficiency. Patients with primary able [46]. Early diagnosis of mild hypothyroidism adrenal insufficiency have a high concentration of permits early intervention, which improves the abili- plasma ACTH at 0800 hours; ACTH levels can be as ty to affect growth velocity and quality of life. high as 4000 pg/ml (880 pmol/l) or even higher. In Free T4 and serum TSH are the best screening tests contrast, plasma ACTH concentrations are low or for thyroid status. Free T4 below the normal range low-normal in patients with secondary or tertiary without TSH elevation is strongly suggestive of cen- adrenal insufficiency.The normal value at 0800 hours tral hypothyroidism. However, some patients with is usually 20 to 80 pg/ml (4.5–18 pmol/l). central hypothyroidism may have free T4 concentra- The approach is somewhat different in patients tions in the lowest third of the normal range [46, 47, who present in hypotensive crisis.These patients may 54]. The first laboratory evidence of central hypothy- have adrenal insufficiency or one of several other roidism may be a small decline in free T4. If further possible disorders. Furthermore, adrenal insufficien- testing confirms hypothyroidism, treatment should cy, if present, may be caused by infection, hemor- be initiated even though free T4 is still within the rhagic diathesis or metastatic disease that requires normal range. This is because the free T4 level is like- prompt diagnosis and treatment. In these patients, ly to be below the individual’s optimal set-point. In measurement of basal serum cortisol,followed by the our own investigation,both the TRH test and the TSH low-dose ACTH stimulation test (see below), pro- surge test were performed for patients whose free T4 vides the most rapid and reliable diagnosis. A basal was in the lowest third of the normal range and plasma ACTH measurement can be ordered at the whose TSH was not elevated.The TRH test confirmed same time, but diagnosis and treatment must pro- 60% of cases of central hypothyroidism after cranial ceed immediately without waiting for the ACTH and irradiation.Measurement of the nocturnal TSH surge cortisol results. confirmed 71% of cases. Measurement of both the The gold standard for diagnosis of ACTH deficien- TSH surge and the response to TRH are optimal in cy is failure of serum cortisol to rise above 20 µg/dl order to identify all cases [54]. Unfortunately, how- (552 nmol/l) in response to insulin-induced or spon- ever, TRH, is no longer available in the United States taneous hypoglycemia.Another method of diagnosis as a test agent. involves the administration of metyrapone to block the adrenal conversion of 11-deoxycortisol to cortisol. This method stimulates the production of ACTH and a secondary increase of 11-deoxycortisol. Failure of the concentration of 11-deoxycortisol to rise above 7 µg/dl (200 nmol/l) in the presence of a low serum 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 70

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cortisol (below 5 µg/dl [138 nmol/l]) signifies ACTH more than 50 Gy of irradiation to the hypothalamus. deficiency [10, 61]. The definitive PRL level should not be drawn in the An attempt to simplify the evaluation of the hypo- hour or two after breast examination or nipple stim- thalamic–pituitary-adrenal axis led to the develop- ulation. ment of the one-hour ACTH test (or high-dose ACTH test), which consists of the administration of ACTH 5.3.9 Diabetes Insipidus (250 µg/m2) by intravenous infusion during a one- minute time frame [55]. Serum cortisol is measured Urine-specific gravity of patients with diabetes in- an hour later and is normally greater than 20 µg/dl sipidus is usually lower than 1.010 (<300 mOsm/l), (552 nmol/l). Patients with complete ACTH deficien- unless the patient is severely dehydrated. In most of cy (in whom the adrenal glands have not been ex- these patients,serum osmolarity is slightly increased, posed to ACTH for 4–10 weeks) fail to respond with a and the plasma concentration of antidiuretic hor- one-hour serum cortisol concentration of more than mone is inappropriately low for the osmolarity. How- 20 µg/dl (552 nmol/l) [64]. In contrast, patients with ever,patients with an intact thirst mechanism may be partial ACTH deficiency or recent onset of complete able to drink sufficiently to avoid laboratory abnor- ACTH deficiency may have a normal serum cortisol mality. Symptoms of polydipsia, polyuria, and noc- response to this dose of ACTH, and ACTH deficiency turia or enuresis may be the only evidence of diabetes may not be detected by this test. insipidus. In partial diabetes insipidus, a water depri- The low-dose ACTH test is the most sensitive test vation test may be needed to establish the diagnosis for partial ACTH deficiency. In this test, a more phys- and rule out other causes of polyuria. iologic dose of ACTH (1 µg/m2) is administered by intravenous infusion over a period of one minute, 5.3.10 Osteopenia and blood for a serum cortisol assay is drawn 20 minutes after the infusion. Peak serum cortisol Osteopenia in cancer survivors may be unrecognized higher than 20 µg/dl (552 nmol/l) is considered nor- in the absence of fractures unless evaluation is per- mal, and peak serum cortisol lower than 18 µg/dl formed. Serum osteocalcin and urine pyridinoline (497 nmol/l) is considered low. Patients with cortisol crosslinks or N-telopeptide do not identify whether peaks between these values have indeterminate there is low bone mineral density. Identification re- results; these patients should be treated with gluco- quires performance of either a dual-energy x-ray ab- corticoids when they are ill and will require further sorptiometry (DEXA), which offers precise estimates evaluation [64]. Further evaluation can include a sec- of bone mineral area density (mg/cm2) at multiple ond low-dose ACTH test or metyrapone administra- sites for the least amount of radiation exposure, tion two months to a year later. or a quantitative computerized tomography (QCT), The low-dose and high-dose ACTH stimulation which measures true volumetric density (mg/cm3) tests have supplanted insulin-induced hypoglycemia of trabecular or cortical bone at any skeletal site. in clinical practice. The results are similar to those T-score may be calculated in reference to normal obtained with insulin-induced hypoglycemia; in ad- young adults (age of peak bone mass is between dition,ACTH tests can be performed without a physi- 20–35 years) and Z-score in reference to age-matched cian being present and are less expensive. normal individuals of the same gender. Results of DEXA must be adjusted for patient height and age. 5.3.8 Hyperprolactinemia 5.3.11 Hypothalamic Obesity Hyperprolactinemia is diagnosed when the serum level of PRL is elevated. The PRL level should be peri- Clinical symptoms are the basis for diagnosing hypo- odically measured in patients with symptoms out- thalamic obesity. These include rapid weight gain lined above (section 5.2.6) and in those who received (Fig. 5.11a), voracious appetite, and aggressive food 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 71

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a b

Figure 5.11 a,b a Hypothalamic Obesity and GH deﬁciency in a boy. b Exogenous obesity in a girl

seeking. Patients may have rapid weight gain for oth- insulin excursions to OGTT. However, these results er reasons (Fig. 5.11b): exogenous steroid use, inac- may be seen in any person who becomes obese. tivity, overfeeding, excessive thirst and drinking of sugared drinks. Obesity in adults is defined as having a body mass index (BMI) of >30 [BMI = wt(kg) / 5.4 Management of Established Problems ht(m2)] (http://nhlbisupport.com/bmi/). Overweight 5.4.1 GH Deficiency in children is defined as having a weight greater than the sex- and age-specific 95th percentile or BMI Standard therapy for GH deficiency is synthetic re- >85th percentile (www.cdc.gov/growthcharts/). Eval- combinant human GH (Fig. 5.12a, b). Any patient uation of these patients includes blood pressure identified with GH deficiency should be evaluated measurement, fasting lipid profile, fasting glucose for possible ACTH deficiency and for central hypo- and insulin level, and oral glucose tolerance testing thyroidism. If ACTH is deficient, adequate cortisol with insulin levels (OGTT). In general, fasting glu- therapy should be started before GH or thyroid ther- cose is normal and fasting insulin is elevated in apy. Patients with GH deficiency who have partial patients with hypothalamic obesity. They have a high or total ACTH deficiency and are receiving subopti- post-prandial insulin level, as well as early and rapid mal hydrocortisone replacement may be at risk for 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 72

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a b

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᭣ Figure 5.12 a–d height, weight and arm span.Arm span is a surrogate a Response to GH therapy in a girl with GH deficiency. measure of height, particularly in patients in whom b Response to GH therapy in a boy with GH deficiency. height measurement may not fully reflect body c Response to GnRH agonist in a boy with precocious growth (e.g. those with scoliosis or a history of spinal puberty. d Response to thyroid hormone in a boy with irradiation). Usually, the GH dose is increased as central hypothyroidism weight gain occurs to maintain a stable dose per kilo- gram of body weight. Serum IGF-I measurements are recommended yearly [17]. After the first two years of GH therapy, if the level of IGF-I surpasses the upper developing cortisol deficiency when GH therapy is limits of normal for the patient’s age and sex, the GH initiated. This is because of the inhibitory effect of dose should be decreased. Evaluation of pubertal GH on 11β-hydroxysteroid dehydrogenase type 1,the stage and screening for development of additional enzyme that converts cortisone to cortisol [70]. endocrinopathies (thyroid, gonadotropins, ACTH) The usual dose of GH in children is 0.15 to should be performed at least annually. Even with GH 0.3 mg/kg per week divided into daily doses and ad- therapy, some childhood cancer survivors do not ministered subcutaneously in the evening. Lower grow as well as expected, a finding that suggests that doses are used in adults [71]. Each dose produces a other factors,such as thyroid hormone deficiency,are pharmacologic level of GH for approximately 12 present. hours. The growth rate in children on GH therapy GH treatment in children is usually safe [72]. Ad- typically increases to above normal for 1–3 years and verse effects are rare and occur soon after therapy is then slows to normal velocity. After 4–5 years of GH initiated. They include pancreatitis, benign intracra- therapy, the adult height SD score of leukemia sur- nial hypertension (pseudotumor cerebri), slipped vivors with GH deficiency usually approaches the capital femoral epiphysis and carpal tunnel syn- height SD score at the time of diagnosis [26]. The drome [3]. Pseudotumor cerebri and carpal tunnel growth response may be poorer in patients who have syndrome are probably caused by sodium and water received total body or spinal irradiation, or in pa- retention. Increases in the growth and pigmentation tients with a disease such as neuroblastoma [19, 42]. of nevi also have been reported [5]. GH therapy does GHRH may be used as an alternative therapy for not increase the risk of brain tumor or leukemia GH deficiency in patients without primary sellar tu- recurrence [26, 43, 68]. In the Childhood Cancer Sur- mors. GHRH therapy, also administered subcuta- vivor Study [63], GH therapy did not appear to in- neously in daily evening doses, elicits a nighttime crease the risk of secondary leukemia or solid malig- pulsatile pattern of GH secretion that approximates nancy in patients who did not received RT. Because the normal pattern. Experience with GHRH therapy all of the evaluable patients who developed a second after cranial irradiation is limited. In one study, nine neoplasm in this study had received RT,the synergis- children who had undergone cranial or craniospinal tic effects of GH and irradiation on the development irradiation at least two years earlier were treated with of the second malignancy could not be discerned twice-daily subcutaneous injections of GHRH for [63]. The absolute number of excess solid tumors one year and then with daily GH injections for attributable to GH (including many benign menin- one year [41]. Both GHRH and GH increased height giomas), if any, will probably be very small (<4/1000 velocity from baseline: GHRH increased height ve- person years at 15 years after diagnosis). locity from 3.3 cm/y to 6.0 cm/y, and GH increased it from 3.3cm/y to 7.5 cm/y. GHRH as therapy has been 5.4.2 LH or FSH Deficiency taken off the market recently in the USA. During GH therapy, evaluation of the growth re- The use of estrogen or testosterone therapy should sponse and adjustment of GH dose should occur not be initiated without careful attention to the pedi- every 4–6 months and include measurement of atric survivor’s growth pattern. Replacement of pu- 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 74

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bertal hormones in a short or slowly-growing adoles- 5.4.3 Precocious Puberty cent can cause fusion of bony growth centers and shorter-than-expected adult height. Such therapy GnRH analogs are the most effective treatments for should be provided only in coordination with the precocious puberty, rapid tempo puberty or normal- pediatric endocrinologist after an assessment of ly-timed puberty that is inappropriate for height. growth potential and treatment of GH or thyroid de- GnRH analogs suppress LH and FSH release from the ficiencies. Initiation of sex steroid therapy in a short pituitary gland through the provision of a steady, adolescent may be delayed until age 15 years to per- rather than a pulsatile, level of GnRH; the pituitary mit response to GH or thyroid hormone therapy and gland stops responding to GnRH when GnRH con- taller adult height. In short adolescents with delayed centrations are steady or unchanging. The use of puberty, a few years of therapy with low-dose sex GnRH analogs to delay pubertal progression opti- steroid therapy is preferable to full replacement.Such mizes adult height potential by permitting the child doses simulate the sex steroid levels observed in the to grow taller without experiencing a rapid change in first year or so of puberty and are less likely than full bone maturation [8] (Fig. 5.12 c). sex steroid replacement to cause inappropriate matu- Treatment with GnRH analogs should be pre- ration of bone age. Girls can be treated with the con- scribed and monitored by a pediatric endocrinolo- jugated estrogen tablets Premarin (0.3 mg every oth- gist [73].GnRH analogs can be administered as a dai- er day) or ethinyl estradiol (5 mcg daily, one quarter ly subcutaneous injection or every four weeks in a of a 20-mcg tablet daily) [47]. Menstrual spotting can sustained or depot preparation. GnRH analog thera- be treated with medroxyprogesterone, 10 mg per day, py is usually continued until patients attain the third for 10 days, followed by the resumption of low-dose percentile for adult height: 152 cm (60 inches) in girls estrogen. Boys can be treated with 45 or 50 mg/m2 and 162 cm (64 inches) in boys. testosterone enanthate injected intramuscularly once each month. After the achievement of a height ac- 5.4.4 Hypothyroidism ceptable to the patient, both boys and girls may benefit from a gradual increase in hormone replacement The standard treatment for TSH deficiency or pri- therapy to the full replacement dose,if there has been mary hypothyroidism is levothyroxine replacement no sex steroid production in recent months. The therapy (Fig. 5.12 d). Thyroid hormone replacement increase to full replacement should take place in 1- to can precipitate clinical decompensation in patients 3-month steps to permit gradual adjustment to the with unrecognized adrenal insufficiency, because hormonal effects. levothyroxine treatment may improve the metabolic Full hormone replacement in adolescent girls who clearance of cortisol. Thus, it is necessary to evaluate have reached their adult height is easily achieved with patients for adrenal insufficiency and, if this condi- regular use of a standard oral contraceptive (28-day tion is present, treat it with hydrocortisone before pill packet).Boys who have attained their adult height initiating thyroid hormone therapy. In patients who can be treated with testosterone (200 mg injected also have ACTH deficiency, we usually initiate corti- intramuscularly every 2 weeks) or with androgen by sol replacement three days before beginning thyroid patch or a topical gel. hormone therapy. The primary medical risk of delayed puberty is de- The typical thyroid hormone replacement dose for layed bone mineralization. Adolescents with delayed infants under three years of age and for healthy chil- or interrupted puberty should receive 1500 mg of dren and adolescents with TSH less than 30 mU/l is elemental calcium and 400 IU of vitamin D per day to levothyroxine 3 mcg/kg orally every morning. Chil- improve bone mineralization. dren over three years of age who have TSH greater than 30 mU/l, or about whom there are concerns regarding medical stability, can begin levothyroxine at a low-dose (0.75mcg/kg by mouth every morning) 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 75

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and increase it by 0.75 mcg/kg per day each month to partial or total ACTH deficiency and are receiving permit a gradual physiologic and psychological ad- suboptimal cortisol or cortisone replacement may be justment to the new metabolic state. Thyroid hor- at risk of developing symptoms of cortisol deficiency mone concentrations should be measured after four when GH therapy is initiated. This is because of the weeks of therapy, due to the fact that levothyroxine inhibitory effect of GH on 11β-hydroxysteroid dehy- has a long half-life (5–6 days). drogenase type 1. Similarly, the initiation of thyroid Unlike primary hypothyroidism, it is not useful hormone therapy in a child with unrecognized or to monitor TSH in patients with central hypothy- under-treated ACTH deficiency also can precipitate roidism. In a prospective study of 37 patients with adrenal crisis. central hypothyroidism, free T4 and free T3 were Patients with ACTH deficiency must receive addi- monitored during therapy and adjusted to achieve tional glucocorticoid during times of illness or stress free T4 in the midnormal range without free T3 ele- (e.g. fever, gastrointestinal illness, injury). The dose vation and without symptoms of hypothyroidism or of additional hydrocortisone that is necessary during hyperthyroidism [14].We usually adjust thyroid hor- times of illness is 30 mg/m2 per day divided into three mone replacement therapy in patients with central doses administered by mouth. Patients whose illness hypothyroidism to maintain the level of free T4 just or injury is severe enough to require emergency care above the middle of the normal range (for example, or hospitalization, and who are unable to retain oral free T4 of 1.4–1.6 ng/dl if the normal range is 0.78– medication or require anesthesia, surgery or both, 1.85 ng/dl). should urgently receive hydrocortisone (100 mg/m2 intramuscularly or intravenously), followed by hy- 2 5.4.5 ACTH Deficiency drocortisone (10–25 mg/m IV every six hours) during management of the critical illness [64]. At stress Patients with ACTH insufficiency require daily hy- doses, hydrocortisone provides some mineralocorti- drocortisone replacement.Hydrocortisone is the pre- coid effect. The hydrocortisone dose should be referred agent for glucocorticoid replacement in chil- duced to the usual replacement therapy dose as soon dren, because it is least likely to impair growth. Pa- as the event is over or the patient’s medical status im- tients with ACTH deficiency do not need mineralo- proves. Tapering of the dose is not necessary if the corticoid replacement, because these hormones are pharmacologic stress doses are used for less than 10 produced by the adrenal gland under the influence of days. the renin-aldosterone system rather than under the Patient and family education is an important com- influence of ACTH. Dexamethasone is not standard ponent of treating patients with ACTH deficiency. for glucocorticoid replacement therapy because it The patient and responsible family members should has a greater potential to suppress growth than does be instructed about the following issues: hydrocortisone. ▬ The nature of the hormonal deficit and the ration- The dose of hydrocortisone for replacement ther- ale for replacement therapy apy is 7–10 mg/m2 per day, divided into two or three ▬ Maintenance medications and the need for doses administered by mouth. For example, a child changes in medications during minor illnesses whose body surface is 0.9 m2 could receive 2.5 mg ▬ When to consult a physician three times per day, or an adult whose body surface is ▬ The need to keep an emergency supply of gluco- 1.5 m2 could receive 5 mg at breakfast and at 1500 corticoids hours plus 2.5 mg at bedtime. The glucocorticoid ▬ The proper stress dose for the patient’s body dose may need to be increased in patients taking weight drugs such as phenytoin, barbiturates, or the newer ▬ When and how to inject glucocorticoids for emer- anticonvulsants, rifampin, mitotane, and aminog- gencies lutethimide, which accelerate hepatic steroid metabolism [13]. Patients with GH deficiency who have 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 76

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Every patient should have at least three pre-prepared at www.medicalert.org (U.S.) or www.medicalert.ca syringes of hydrocortisone (Solu-Cortef): one at (Canada). home, one at work or school, and one in the car. In addition, it is wise for the patient to carry a syringe 5.4.6 Hyperprolactinemia at all times. The syringes can be obtained either as 250 mg/2 ml vials or prepared by a pharmacist in reg- The elevation of prolactin in excess of 100 ng/ml ular 1 ml syringes from a multidose vial. The patient may lead to symptoms. Dopamine agonists such as and parents must be instructed regarding the correct bromocriptine and cabergoline are the treatment of dose. The injectable stress dose is 10 times the daily choice to suppress PRL secretion and restore normal hydrocortisone dose. Thus, typical doses for children gonadal function. Cabergoline, in general, is more would be 50–125 mg (0.4 to 1.0 ml of a 250 mg/2 ml potent, much longer acting and better tolerated than solution). Unused syringes should be replaced every bromocriptine. The usual starting dose is 0.25 mg year or sooner if the solution inside becomes cloudy twice a week. or discolored. The patient and one or more responsible family or 5.4.7 Diabetes Insipidus household members should be instructed to inject the contents of a syringe subcutaneously or intra- The drug of choice for hormone replacement is muscularly anywhere on the patient’s body during desmopressin acetate or DDAVP®, which can be any of the following circumstances: given by subcutaneous injection, nasal insufflations or orally in one or two daily doses.Oral desmopressin ▬ The patient has a major injury with substantial is available in tablets containing 0.1 or 0.2 mg. To blood loss, fracture, or neurogenic shock avoid water intoxication, successive doses should ▬ The patient has nausea and vomiting and cannot not be given until a brief diuresis has occurred retain oral medications at least once daily. By giving a dose at bedtime, sleep ▬ The patient has symptoms of acute adrenal insuf- disturbance by nocturia can be avoided. The stan- ficiency dard dose of 1.25–5.0 µg intranasally, or 0.1–0.6 mg ▬ The patient is found unresponsive orally, will usually achieve rapid urinary concentration that lasts approximately 8–24 hours (Fig. 5.13). Instructions should include the need to obtain med- The process of starting desmopressin therapy may ical help immediately after injection of the stress require close monitoring of the volume of fluid dose. The patient should be instructed to have a low taken in and urine output. Several weeks of dose threshold for injecting the hydrocortisone: if the pa- adjustment may be required before achieving a stable tient feels the injection might be necessary, then it dose (Fig. 5.13). In patients with partial diabetes should be injected, and medical attention should be insipidus, chlorpropamide may be used to enhance sought. It is unlikely, however, that a patient will need the effect of the limited antidiuretic hormone that the stress dose of hydrocortisone more than two or remains. three times per year, and most patients go for years without needing it. Used hydrocortisone syringes 5.4.8 Osteopenia should be replaced immediately. Every patient should wear a medical alert (Medic Osteopenia after cancer therapy may be prevented by Alert) bracelet or necklace and carry the Emergency maintaining optimal calcium (1500 mg daily) and Medical Information Card that is supplied with it. vitamin D (400 units daily) in the diet. Nutritional Both should indicate the diagnosis, the daily medica- supplements may be needed in cases of osteopenia tions and doses and the physician to call in the event that is unresponsive to behavioral and dietary man- of an emergency. Patients can enroll in Medic Alert agement. In addition, early diagnosis and replace- by calling 800–432–5372 or through the internet ment of hormone deficiencies will benefit bone min- 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 77

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obesity in individual patients. If the obesity is exogenous, and hyperinsulinemia is a consequence of the obesity and insulin resistance, lifestyle changes with or without metformin should resolve the problem. If the obesity is hypothalamic and the hyperinsulinism is the cause of the increased appetite, metformin use may lead to hypoglycemia and no reduction in appetite. Octreotide is a somatostatin analog that binds to the somatostatin receptor. It not only decreases insulin secretion from pancreatic β-cells, it also decreases growth hormone and TSH secretion from the pituitary gland. If the obesity is exogenous and high insulin levels reﬂect insulin resistance, the patient may become diabetic with octreotide therapy. If the obesity is hypothalamic, octreotide will decrease insulin secretion leading to reduced appetite, weight control and an improved sense of well being [28, 29]. Octreotide is taken as 2–3 injections daily. Side effects may include gallstones. Patients treated with octreotide may also require therapy with growth hormone and thyroid hormone.

Figure 5.13 References Urine output with inadequate DDAVP treatment (top and middle panels) and improved control of urine out- 1. Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, put with adjusted DDAVP dosing (bottom panel) Bonert V, Stavrou S, Kleinberg DL, Chipman JJ, Hartman ML (2002) Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 87:2067–2079 2. Blatt J, Bercu BB, Gillin JC, Mendelson WB, Poplack DG eralization.In the event of fractures,bisphosphonates (1984) Reduced pulsatile growth hormone secretion in may be beneficial. children after therapy for acute lymphoblastic leukemia. J Pediatr 104:182–186 3. Blethen SL, Allen DB, Graves D, August G, Moshang T, 5.4.9 Hypothalamic Obesity Rosenfeld R (1996) Safety of recombinant deoxyribonucle- ic acid-derived growth hormone: The National Coopera- Part of the therapy for hypothalamic obesity involves tive Growth Study Experience. J Clin Endocrinol Metab early identification and initiation of preventive meas- 81:1704–1710 ures, including caloric and dietary control and main- 4. Boepple PA, Crowley WF Jr (1996) Precocious puberty. In: tenance of regular exercise. In addition to maintain- Adashi EY, Rock JA, Rosenwaks Z (eds) Reproductive ing these lifestyle choices, several drug therapies endocrinology, surgery, and technology, vol 1. Lippincott- Raven, Philadelphia, p 989 have been used pragmatically or in research efforts. 5. Bourguignon JP,Pierard GE, Ernould C, Heinrichs C, Craen These include Dexedrine, Ritalin, metformin, and M, Rochioccioli P,Arrese JE, Franchimont C (1993) Effects octreotide. Dexedrine and Ritalin are taken orally of human growth hormone therapy on melanocytic naevi. and act as stimulants with the side effect of appetite Lancet 341:1505–1506 suppression (in this situation, beneficial). Metformin 6. Brauner R, Malandry F, Rappaport R, Zucker JM, Kalifa C, Pierre-Kahn A, Bataini P, Dufier JL (1990) Growth and is taken orally twice a day and acts as a sensitizer to endocrine disorders in optic glioma. Eur J Pediatr 149: insulin effects and may serve to probe the etiology of 825–828 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 78

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7. Burstein S (1994) Growth disorders after cranial radiation 20. Kaste SC, Jones-Wallace D, Rose SR, Boyett JM, Lustig RH, in childhood. J Clin Endocrinol Metab 78:1280–1281 Rivera GK, Pui CH, Hudson MM (2001) Bone mineral 8. Cassorla F,Mericq V,Eggers M,Avila A,Garcia C,Fuentes A, decrements in survivors of childhood acute lymphoblastic Rose SR, Cutler GB Jr (1997) Effects of luteinizing hor- leukemia: frequency of occurrence and risk factors for mone-releasing hormone analog-induced pubertal delay their development. Leukemia 15:728–734 in growth hormone (GH)-deficient children treated with 21. Lam KS, Tse VK, Wang C,Yeung RT, Ho JH (1991) Effects of GH: preliminary results. J Clin Endocrinol Metab 82:3989– cranial irradiation on hypothalamic-pituitary function – a 3992 5-year longitudinal study in patients with nasopharyngeal 9. Chrousos GP (1995) The hypothalamic-pituitary-adrenal carcinoma. Q J Med 78:165–176 axis and immune-mediated inflammation. N Engl J Med 22. 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Growth Hormone Research Society (2000) Consensus Broome DC, Smith K, Li H, Hudson MM, Heideman RL, guidelines for the diagnosis and treatment of growth hor- Kun LE (1999) Hypothalamic obesity caused by cranial in- mone (GH) deficiency in childhood and adolescence: sult in children: altered glucose and insulin dynamics and summary statement of the GH Research Society. J Clin reversal by a somatostatin agonist. J Pediatr 135:162–168 Endocrinol Metab 85:3990–3993 29. Lustig RH, Post SR, Srivannaboon K, Rose SR, Danish RK, 18. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony Burghen GA, Xiong X, Wu S, Merchant TE (2003) Risk fac- CJ, Bhapkar MV, Koch GG, Hasemeier CM (1997) Sec- tors for the development of obesity in children surviving ondary sexual characteristics and menses in young girls brain tumors. J Clin Endocrinol Metab 88:611–616 seen in office practice: a study from the Pediatric Research 30. Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, in Office Settings network. Pediatrics 99:505–512 Kaste SC, Schreiber RE, Rai SN, Lensing SY,Wu S, Xiong X 19. Hovi L, Saarinen-Pihkala UM, Vettenranta K, Lipsanen M, (2003) Octreotide therapy of pediatric hypothalamic Tapanainen P (1999). Growth in children with poor-risk obesity: a double-blind, placebo-controlled trial. J Clin neuroblastoma after regimens with or without total body Endocrinol Metab 88:2586–2592 irradiation in preparation for autologous bone marrow 31. Merchant TE, Pritchard DL, Vargo JA, Sontag MR (2001) transplantation. Bone Marrow Transplant 24:1131–1136 Radiation therapy for the treatment of childhood medulloblastoma: the rationale for current techniques,strategies, and dose-volume considerations. Electro Med 69:69–71 05_Schwartz_Neuroendocrine 27.01.2005 9:39 Uhr Seite 79

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